Gamma Aminobutyric Acidergic and Neuronal Structural Markers in the Nucleus Accumbens Core Underlie Trait-like Impulsive Behavior

Background: Pathological forms of impulsivity are manifest in a number of psychiatric disorders listed in DSM-5, including attentiondeficit/
hyperactivity disorder and substance use disorder. However, the molecular and cellular substrates of impulsivity are poorly
understood. Here, we investigated a specific form of motor impulsivity in rats, namely premature responding, on a five-choice serial
reaction time task.
Methods: We used in vivo voxel-based magnetic resonance imaging and ex vivo Western blot analyses to investigate putative
structural, neuronal, and glial protein markers in low-impulsive (LI) and high-impulsive rats. We also investigated whether messenger
RNA interference targeting glutamate decarboxylase 65/67 (GAD65/67) gene expression in the nucleus accumbens core (NAcbC) is
sufficient to increase impulsivity in LI rats.
Results: We identified structural and molecular abnormalities in the NAcbC associated with motor impulsivity in rats. We report a
reduction in gray matter density in the left NAcbC of high-impulsive rats, with corresponding reductions in this region of glutamate
decarboxylase (GAD65/67) and markers of dendritic spines and microtubules. We further demonstrate that the experimental reduction of
de novo of GAD65/67 expression bilaterally in the NAcbC is sufficient to increase impulsivity in LI rats.
Conclusions: These results reveal a novel mechanism of impulsivity in rats involving gamma aminobutyric acidergic and structural
abnormalities in the NAcbC with potential relevance to the etiology and treatment of attention-deficit/hyperactivity disorder and related
disorders.